Thiazole derivatives as modulators of g protein-coupled receptors

Abstract

The invention provides compounds of formula (IA) or (IB) and pharmaceutical compositions thereof, which are useful for modulating G protein-coupled receptor 120 (GPR120), and methods for using such compounds to treat, ameliorate or prevent a condition associated with abnormal or deregulated GPR120.

1 . A compound of Formula (1A) or (1B): 
     
       
         
         
             
             
         
       
       or pharmaceutically acceptable salts thereof, wherein: 
       L 1  is a bond or —CR 3   2 —O—; 
       L 2  is a bond or NR 3 ; 
       R 1  is OR, or an optionally substituted C 1-6  alkyl, C 2-6  alkenyl or C 3-6  alkynyl; 
       R 2  is NR 3 —(CR 3   2 ) m R 4  or R 4 ; 
       R 3  is H or C 1-6  alkyl; 
       R 4  is C 3-7  cycloalkyl, aryl, heteroaryl or heterocyclic ring containing N, O or S, each of which is optionally substituted with halo, hydroxyl, nitro, OR, SR, NR 2 , NR 3 —(CR 3   2 ) m —R 4 , or an optionally substituted C 1-6  alkyl, C 2-6  alkenyl or C 3-6  alkynyl; or 
       R 3  and —(CR 3   2 ) m —R 4  together with N in NR 3 —(CR 3   2 ) m —R 4  form an optionally substituted heterocyclic ring; 
       each R is H, an optionally substituted C 1-6  alkyl or —(CR 3   2 ) m —R 4 ; and 
       m and n are independently 0-4. 
     
   
   
       2 . The compound of  claim 1 , wherein said compound is of Formula (2A) or (2B): 
     
       
         
         
             
             
         
       
       wherein each n is 0. 
     
   
   
       3 . The compound of  claim 1 , wherein R 2  is an optionally substituted phenyl, piperidinyl or pyridyl. 
   
   
       4 . The compound of  claim 1 , wherein said compound is of Formula (3A) or (3B): 
     
       
         
         
             
             
         
       
       wherein Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 9  and Z 10  are independently CR 5  or N; and 
       R 5  is H halo, hydroxyl, nitro, OR, SR, NR 2 , NR 3 —(CR 3   2 ) m —R 4 , or an optionally substituted C 1-6  alkyl, C 2-6  alkenyl or C 3-6  alkynyl. 
     
   
   
       5 . The compound of  claim 4 , wherein each Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 9  and Z 10  is CR 5 . 
   
   
       6 . The compound of  claim 4 , wherein one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 9  and Z 10  is N. 
   
   
       7 . The compound of  claim 1 , wherein said compound is of Formula (4A) or (4B): 
     
       
         
         
             
             
         
       
       wherein R 3  is H or C 1-6  alkyl; 
       R 4  is a 5-6 membered aryl or heteroaryl; or 
       R 3  and —(CR 3   2 ) m —R 4  together with N in NR 3 —(CR 3   2 ) m —R 4  form an optionally substituted 4-7 membered heterocyclic ring; and 
       m is 0 or 1. 
     
   
   
       8 . The compound of  claim 7 , wherein R 4  is phenyl or R 3  and —(CR 3   2 ) m —R 4  together with N in NR 3 —(CR 3   2 ) m —R 4  form an optionally substituted piperidinyl. 
   
   
       9 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to  claim 1 . 
   
   
       10 - 15 . (canceled) 
   
   
       16 . A method for modulating G protein-coupled receptor 120 (GPR120) comprising administering to a cell or tissue system, a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent, thereby modulating said GPR120. 
   
   
       17 . The method of  claim 16 , wherein said compound is a GPR120 agonist. 
   
   
       18 . A method for treating a condition mediated by G protein-coupled receptor 120 (GPR120), comprising administering to a mammalian subject, an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and optionally with a second therapeutic agent, thereby treating said condition. 
   
   
       19 . The method of  claim 18 , wherein said condition is diabetes, dyslipidemia, obesity or anorexia. 
   
   
       20 . The method of  claim 19 , wherein said diabetes is diabetes mellitus. 
   
   
       21 . The method of  claim 19 , wherein said dyslipidemia is hyperlipidemia.